In response to RFA AI-94-20, Dr. Natelson and colleagues propose to continue the study of the CFS Cooperative Research Center (CRC). The central theme and goal of the Center is to use subgroups of CFS patients stratified by biological and neuro/psychiatric abnormalities to gain insight into etiology and treatment. The purpose of the Center will be to continue integrating the diagnostic capabilities of state-of-the-art virology and immunology researchers with a group of physicians and scientists expert at physiological evaluation and psychologists expert at psychiatric and cognitive assessment. The study approach moves from the genetic and cellular level of viral reactivation and cytokine production, to the organ level of physiological function, and to the system level to evaluate the neuro/psychological illness pattern, and fitness status of the patient. In the first 3 years of support, modifications of the Center for Diseases Control and Prevention (CDC) criteria were used to identify a group of severely ill CFS patients with sudden onset and no psychiatric morbidity who showed more cognitive impairment and more abnormal viral or immunologic parameters than CFS patients with gradual onset or current psychiatric diagnosis. This fruitful strategy will be extended to include a group of less severely ill CFS patients to allow comparisons between mild and severe CFS. A three-pronged strategy has been proposed for the next 5 years of the Center's activities. First, ideas synthesized from data obtained to date will fuel new studies aimed at understanding the abnormalities or causes of CFS. The second tier provides for biannual longitudinal testing to identify predictors of recovery in CFS. The third tier is an intervention trial of fitness training to determine if breaking the cycle of inactivity can normalize physiologic, cognitive, viral/immunologic impairments and improve health. These highly collaborative studies represent integration of medicine, psychology and physiology. One Core Unit will provide administrative and data analytic services to all research projects.